1. Technical Field
The present invention relates to a novel class of compounds, methods of synthesis and uses thereof. The present invention also relates to solid drug/active agent nanoparticles having compounds of the present invention associated with the surface thereof.
2. Background Art
The long-term stabilization of nanosuspensions is an uphill battle against the thermodynamics of a metastable, dispersed system. Given enough time, all suspensions will eventually coalesce. Stability therefore rests on the ability to kinetically impede this process. Instability can result from a shift in size distribution to larger particles (Ostwald ripening), irreversible agglomeration, secondary and polymorphic nucleation. In order to obtain a stable suspension, the considerable potential energy created by the large interface between the solid and the surrounding medium must be reduced by adding surface-active agents. Surface stabilization may be achieved by using charged amphiphiles that migrate to the solid-liquid interface and provide an electrostatic barrier to particle agglomeration. Non-ionic polymers may also aid in surface stabilization. Polymeric surfactants such as poloxamer 188, a triblock co-polymer of ethylene glycol and propylene glycol, are very effective non-ionic stabilizers because of multiple attachments of hydrophobic domains at the particle surface.
Entropically, the probability of detachment of all of these hydrophobic moieties is very low at room temperature, thus providing a strong surface affinity (Alexandridis, P.; Hatton, T. A., Poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymer surfactants in aqueous solutions and at interfaces: thermodynamics, structure, dynamics, and modeling (Review) in Colloids and Surfaces A: Physicochem. Eng. Aspects, volume 96, pages 1-46, (1995)). Non-ionic surfactants may also create a hydration zone, a layer of tightly bound water molecules around each particle. When two particles meet, work is required to dislodge this water layer because of osmotic forces. Other entropic factors are also involved. The hydrophobic domains of the surfactant associate with the particle surface, with pendant hydrophilic domains extending into the aqueous medium. Attraction between particles necessitates the intertwining of these pendant chains leading to a restriction in chain mobility, and hence an unfavorable lowering of entropy (Lee, R. W., Shaw, J. M., McShane, J., Wood, R. W.,. Particle size reduction. In: Liu, R. (Ed.), Water-insoluble drug formulation, Interpharm, p. 478 (2000b.)). This type of stabilization (“steric”), may provide an effective barrier to aggregation. Often, however, a combination of non-ionic and electrostatic stabilization is required to achieve desired particle stability. Glycol copolymers may suffer from reduced solubility in water at high temperatures, which leads to particle aggregation. This results from thermally induced cleavage of hydrogen bonds between the hydrated polymer and water, leading to formation of visible polymer aggregates (“cloud point”). The ability to autoclave such formulations is limited if the cloud point lies below the sterilization temperature (121° C.). Addition of cloud-point modifiers, usually anionic surfactants such as sodium dodecyl sulfate, may raise the cloud point and enhance stability at high temperature (See Lee et al., Particle size reduction, pages 487-488.). Polysorbates (Tweens), poloxamines and poloxamers have been used as non-ionic surfactants. Bile salts (e.g., sodium cholate) and alkyl sulfonates (sodium dodecyl sulfate, sodium dioctylsulfosuccinate, and sodium lauryl sulfate, for example) have been effectively used as ionic surfactants.
It is therefore advantageous to provide both a block copolymeric surfactant with multiple hydrophobic domains as well as provide a charged, amphiphilic surfactant (secondary, ionic surfactant) that sets up a surface charge on the particles, thereby preventing interparticle approach because of electrostatic repulsion. One example of a secondary, ionic surfactant is sodium dodecylsulfonate. Another example is dioctyl sulfosuccinate. However, one then relies on non-covalent, van der Waals interactions between the ionic surfactant and the non-ionic, polymeric surfactant. The potential exists for inadequate suspension stability because of incomplete association of the secondary (ionic) surfactant with the primary (nonionic) surfactant, and thus ineffective interaction of the ionic surfactant with the particle surface.
The present invention provides a solution to the problem by the provision of compounds comprising a non-ionic polymer covalently linked to an anionic sulfonate. This novel class of compounds, among other properties, ensures that the anionic portion is always tied to the polymer, which is in turn strongly bound to the particle surface by the entropic and enthalpic forces described above.
Wong, et al. (U.S. Pat. No. 5,565,188, Polyalkylene block copolymers as surface modifiers for nanoparticles) discloses a composition containing nanoparticles having a surface modifier wherein the surface modifier is a block copolymer containing one or more polyoxyethylene blocks and one or more polyoxy (higher alkylene) blocks and wherein at least some of the blocks are linked together by a linking group characterized in that the linking group is an oxymethylene group. The present invention compounds are, in contrast to the '188 compounds, sulfonates and are not cross-linked.
Wong, et al. (U.S. Pat. No. 5,569,448, Sulfated nonionic block copolymer surfactants as stabilizer coatings for nanoparticle compositions) disclose a composition comprised of nanoparticles containing a therapeutic or diagnostic agent having a surface modifier adsorbed on the surface thereof, wherein said composition is autoclavable and after autoclaving the nanoparticles have an average particle size of less than 500 nm, and wherein the surface modifier is a triblock copolymer having the structure:
where Q is a sulfate group, R is a hydrogen or metal ion, x is 15-700, y is 5-200, and z is 15-700. The polymer backbone is thus a block co-polymer of ethylene glycol and 1,2-butylene glycol. The present invention pendent groups, Q, are sulfonate, not sulfate as those disclosed in the '448 patent. Organic sulfates demonstrate a completely different chemistry and pharmacology than sulfonates. For example, the sulfates are more chemically reactive (sulfate is a good leaving group in nucleophilic displacement reactions) and more toxic because of the ability of such reagents to potentially act as alkylating agents [(a) Dyer, S. D.; Lauth, J. R.; Moral, S. W.; Herzog, R. R.; Cherry, D. S., Development of a chronic toxicity structure activity relationship for alkyl sulfates. Environ. Toxic. Chem., volume 12, pages 295-303 (1997); and (b) Druckrey, H.; Kruse, H.; Preussmann, R.; Ivankovic, S.; Landschutz., C., Carcinogenic alkylating substances, Alkyl halogenides, sulfates, sulfonates and strained heterocyclic compounds. Z. Krebsforsch., volume 74, pages 241-270 (1970).]. Sulfonate salts, on the other hand, are more stable, nearly chemically inert, and thus less toxic.